Benzothiophene aromaticity

The major part of the sulfur contained in crude petroleum is distributed between the heavy cuts and residues (Table 8.10) in the form of sulfur compounds of the naphthenophenanthrene or naphthenoanthracene type, or in the form of benzothiophenes, that is, molecules having one or several naphthenic and aromatic rings that usually contain a single sulfur atom. 

Figure 14.19 Typical GC chromatogram of the separated di-aromatics fraction of a middle distillate sample Peak identification is as follows 1, naphthalene 2, 2-methylnaphthalene 3, 1-methylnaphthalene 4, biphenyl 5, C2-naphthalenes 6, C3-naphthalenes 7, C4-naph-thalenes 8, C5+-naphthalenes 9, benzothiophene 10, methylbenzothiophenes 11, C2-ben-zotliiopIrenes. Note the clean baseline between naphthalene and the methylnaphthalenes, which means that no overlap with the previous (mono-aromatics) fraction has occuned.

Thiophenes continue to play a major role in commercial applications as well as basic research. In addition to its aromatic properties that make it a useful replacement for benzene in small molecule syntheses, thiophene is a key element in superconductors, photochemical switches and polymers. The presence of sulfur-containing components (especially thiophene and benzothiophene) in crude petroleum requires development of new catalysts to promote their removal (hydrodesulfurization, HDS) at refineries. Interspersed with these commercial applications, basic research on thiophene has continued to study its role in electrocyclic reactions, newer routes for its formation and substitution and new derivatives of therapeutic potential. New reports of selenophenes and tellurophenes continue to be modest in number. 

The oxidation of thiophene and its derivatives with H202 was studied using a Ti-Beta molecular sieve. The oxidation product is very dependent from the aromaticity of model compounds. The thiophene oxidation product was mostly sulfates and the benzothiophene oxidation product was benzothiophene sulfone. Oxidation of mono and di-alkyl thiophenes also produced sulfates and sulfones. The diffusivity and aromaticity of the relevant sulfur compounds, intermediates and stable product, as well as the proposed new mechanism of oxidation will be discussed. This proposed new reaction pathway is different from current literature, which reports the formation of sulfones as a stable oxidation product. 

Pinney et al. reported the synthesis of benzothiophene CA4 analogs and an example synthesis is given in Scheme 38 [83]. Benzothiophene (145) was produced by reacting aromatic thiol 146 with a-bromoacetophenone 147 to generate the sulfide 148. Compound 148 was then cyclized to the benzothiophene 149 using polyphosphoric acid and heat. Formation of 145 was achieved by Friedel-Crafts aroylation of 149 with the methoxybenzoyl chloride 144. 

Finally, a variety of alternative aromatic systems were evaluated in an effort to identify surrogates for the indole. Replacement by benzothiophene, indazole or substituted phenyl groups severely reduced or abolished activity in vitro, emphasizing the subtle electronic and steric factors governing the aromatic binding site (compounds not shown). 

The method described in this preparation of mesitoic acid avoids the preparation of bromomesitylene,13 and the yield of acid is essentially the same as that from the two-step synthesis.2-13 This procedure appears to be general and can be used to prepare such acids as a- and /3-naphthoic acids,14 cumenecarboxylic acid, 2,5-dimethylbcnzoic acid, and durenecarboxylic acid. Carboxylic acids could not be obtained from benzothiophene, vera-trole, -dimethoxybenzene, and ferrocene under the conditions of this reaction. Although there has been no exhaustive study, this procedure is probably applicable to a variety of aromatic compounds, especially alkylated aromatics. Aromatic compounds which readily undergo oxidation, e.g., ferrocene, catechol, and hydroquinone, do not lend themselves to this method. 

Oxazoles and benzoxazoles are viable participants in the heteroaryl Heck reactions. In their monumental work published in 1992, Ohta and colleagues demonstrated that oxazoles and benzoxazoles, along with other rc-sufficient aromatic heterocycles such as furans, benzofurans, thiophenes, benzothiophenes, pyrroles, thiazole and imidazoles, are acceptable recipient partners for the heteroaryl Heck reactions of chloropyrazines [22b]. Therefore, treatment of 2-chloro-3,6-diethylpyrazine (27) with oxazole led to regioselective addition at C(5), giving rise to adduct 28. By contrast, a similar reaction between 2-chloro-3,6-diisobutylpyrazine (29) and benz[fc]oxazole took place at C(2) exclusively to afford pyrazinylbezoxazole 30. 

On converting 1-benzothiophene into 1-phenyl-1-benzothiophenium triflate (95), this salt becomes a dienophile and reacts readily with cyclopentadiene or 1,3-diphenylisobenzofuran to give the adduct 96 (Scheme 45).143 This example of the dienophilic nature of the double bond in the benzothiophene ring arises from reduced aromaticity. 

The combination of [IrCl(cod)Cl]2 complex with P(t-Bu)3 efficiently catalyzes aromatic homologation using internal alkyne [70]. For example, the reaction of benzoyl chloride 153 with 4-octyne 154 afforded 1,2,3,4-tetrapropylnaphthalene 155 (Equation 10.41). The reaction with 2-thenoyl and 2-naphthoyl chlorides also affords benzothiophene and anthracene, respectively, in high yields. The reaction would proceed as follows (Scheme 10.9) (i) oxidative addition of aroyl chloride... 

Thiophene as a compound is not found in high concentration in crude oil. However, benzothiophenes and other aromatic thiophenes are critical components of high-sulfur crude oil. Also, thiophenes are present in relatively high concentrations in oils containing increased percentages of aromatics, asphaltenes, and resins. 

A related approach has been used for the synthesis of poly(thiaacene)s, which are novel helical aromatic polymers comprised of fused benzothiophene rings, poly(thiaheterohelicene) <20050L755>. 

Two-ring aromatic heterocycles containing one heteroatom Indole, benzofuran, benzothiophene Quinoline, isoquinoline... 

In the copper catalyzed aromatic nucleophilic substitution of aryl halides bromoindole derivatives were converted to the appropriate cyanoindoles. Both 5-bromoindole and its 7V-tosyl derivative gave excellent yields, when a substoichiometric amount potassium iodide was added to the reaction mixture (6.80.), Pyrazole and benzothiophene showed a similar reactivity. The role of the added iodide is to activate the aromatic system through a bromine-iodine exchange.111... 

In describing catalytic activities and selectivities and the inhibition phenomenon, we will use a common format, where possible, which is based on a common reaction pathway scheme as outlined in Scheme 1. In contrast to the simple one- and two-ring sulfur species from which direct sulfur extrusion is rather facile, in the HDS of multiring aromatic sulfur compounds such as dibenzothiophene derivatives, the observed products are often produced via more than one reaction pathway. We will not discuss the pathways that are specific for thiophene and benzothiophene as this is well represented in the literature (7, 5, 8, 9) and, in any event, they are not pertinent to the reaction pathways involved in deep HDS processes whereby all of the highly reactive sulfur compounds have already been completely converted. 

The metabolism of thiophene (100) was first studied in 1886 by Heffter (1886MI10900), who administered it orally to dogs and noted the increased output of ethereal sulfates in urine. This is typical of aromatic hydrocarbons conversion to phenolic products which are excreted in urine as sulfate conjugates. When fed to rabbits, there was no increase in the ethereal sulfate output, but there was some indirect evidence of the presence in urine of dihydrodiols and thienylmercapturic acids (45MI10900). This was confirmed by Bray and coworkers (71MI10906,68BJ(109)11P>, who studied thiophene and benzothiophene metabolism in rabbits and rats. The only identifiable metabolites in urine were the thienylmercapturic acids (101) and (102), which are probably formed via conjugation of the intermediate... 

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